Synthesis and Antimicrobial Evaluation of Amino Acid Naphthoquinone Derivatives as Potential Antibacterial Agents
Lluvia Itzel López-López, Ernesto Rivera-Ávalos, Cecilia Villarreal-Reyes, Fidel Martínez‐Gutiérrez, Denisse de Loera
Abstract
<b><i>Background:</i></b> The synthesis and biological evaluation of 1,4-naphthoquinone derivatives are of great interest since these compounds exhibit strong antibacterial, antifungal, antimalarial, and anticancer activities. The electronic properties of naphthoquinones are usually modulated by attaching functional groups containing nitrogen, oxygen, and sulfur atoms, which tune their biological potency and selectivity. <b><i>Methods:</i></b> A series of 13 amino acid 1,4-naphthoquinone derivatives was synthesized under assisted microwave and ultrasound conditions. The antibacterial activity of compounds was tested against American Type Culture Collection (ATCC): <i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>, <i>Staphylococcus aureus</i>, and <i>Enterococcus faecalis</i>, as well as 2 multidrug resistant pathogens: <i>E. coli</i> and <i>S. aureus</i> from clinical isolated. Minimal inhibitory concentration (MIC) was determined using the broth microdilution method. <b><i>Results:</i></b> MIC of derivatives 4–11, 14, and 16 showed antimicrobial activity against Gram-positive and Gram-negative bacteria. Antimicrobial activities of the compounds 4–8 and 14 were ≤MIC 24.7 μg mL<sup>−1</sup> against all the reference strains; even more, compound 6 showed the most potent activity with an MIC of 3.9 μg mL<sup>−1</sup> on <i>S. aureus</i>. On the clinical isolated, the compounds 7, 8, and 14 showed an MIC of 49.7 and 24.7 μg mL<sup>−1</sup> against <i>S. aureus</i> and <i>E. coli</i>, respectively. About ADME properties and Osiris analysis, the compounds 4–16 presented high gastrointestinal absorption and good characteristics for oral bioavailability, and compound 14 was the less toxic. <b><i>Conclusion:</i></b> Amino acid 1,4-naphthoquinone derivatives showed good in vitro antibacterial activity against clinical strains, and modifications on C-3 with a chloride atom enhanced the efficiency against the same pathogens.